Singh Natalia N, O'Leary Collin A, Eich Taylor, Moss Walter N, Singh Ravindra N
Department of Biomedical Science, Iowa State University, Ames, IA, United States.
Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, United States.
Front Mol Biosci. 2022 Jul 1;9:928581. doi: 10.3389/fmolb.2022.928581. eCollection 2022.
Humans contain two nearly identical copies of genes, and . Deletion or mutation of causes spinal muscular atrophy (SMA), one of the leading genetic diseases associated with infant mortality. is unable to compensate for the loss of due to predominant exon 7 skipping, leading to the production of a truncated protein. Antisense oligonucleotide and small molecule-based strategies aimed at the restoration of exon 7 inclusion are approved therapies of SMA. Many cis-elements and transacting factors have been implicated in regulation of exon 7 splicing. Also, several structural elements, including those formed by a long-distance interaction, have been implicated in the modulation of exon 7 splicing. Several of these structures have been confirmed by enzymatic and chemical structure-probing methods. Additional structures formed by inter-intronic interactions have been predicted by computational algorithms. genes generate a vast repertoire of circular RNAs through inter-intronic secondary structures formed by inverted Alu repeats present in large number in genes. Here, we review the structural context of the exonic and intronic cis-elements that promote or prevent exon 7 recognition. We discuss how structural rearrangements triggered by single nucleotide substitutions could bring drastic changes in exon 7 splicing. We also propose potential mechanisms by which inter-intronic structures might impact the splicing outcomes.
人类含有基因 和 的两个几乎相同的拷贝。基因 的缺失或突变会导致脊髓性肌萎缩症（SMA），这是一种与婴儿死亡率相关的主要遗传性疾病。由于主要外显子7跳跃，基因 无法补偿基因 的缺失，导致产生截短的蛋白质。旨在恢复外显子7包含的反义寡核苷酸和基于小分子的策略是SMA的获批疗法。许多顺式元件和反式作用因子参与了外显子7剪接的调控。此外，包括由长距离相互作用形成的结构在内的几种结构元件也参与了外显子7剪接的调节。其中一些结构已通过酶促和化学结构探测方法得到证实。通过计算算法预测了由内含子间相互作用形成的其他结构。基因 通过基因中大量存在的反向Alu重复序列形成的内含子间二级结构产生大量的环状RNA。在这里，我们综述了促进或阻止外显子7识别的外显子和内含子顺式元件的结构背景。我们讨论了单核苷酸取代引发的结构重排如何在外显子7剪接中带来剧烈变化。我们还提出了内含子间结构可能影响剪接结果的潜在机制。
